The role of the Beta/A4-amyloid precursor protein gene (APP) on Chr 21 in Alzheimer's disease(AD) is not clear. Two lines of evidence suggest a pivotal role for APP in AD. First, individuals with Down's syndrome (trisomy 21) exhibit accelerated development of the neuropathological features of AD, including abundant amyloid plaques. Overexpression of APP may be responsible for AD-like changes in trisomy 21, though there is no direct evidence that this is the case. Second, linkage between a missense mutation at APP residue 717 and early onset familial AD (FAD) recently has been demonstrated. Unfortunately, no mouse model exists that recapitulates the features of AD. Results from transgenic (Tg) muse experiments on the neurodegenerative diseases caused by prions suggest that the key to mimicking the pathological changes of AD in short lived rodents is obtaining dramatic overexpression of the proteins involved. One line of Tg mice with modest overexpression of APP695 encoded in a minigene construct is currently available. By use of a cosmid transgenic expression vector (cosTet), developed to express hybrid prion protein genes, additional Tg line overexpressing the 695, 751, and 770 isoforms of APP will be produced. By creating APP 'cassettes' for insertion into cosTet, FAD-linked mutations and the mutation linked with hereditary cerebral hemorrhage with amyloidosis-Dutch can be introduced into the expression vector. This will allow testing the hypothesis that these mutations cause disease. Because it is possible that APP overexpression is not a proximal cause of AD, experiments are included that have the potential to induce AD-like changes in Tg mice. Mouse neurological mutations that cause neurodegeneration will be combined with APP transgenes to test the hypothesis that progressive death of cells overexpressing APP initiates Beta-amyloid accumulation and plaque formation. Similar experiments using neurotropic retrovirus or scrapie prions as the neurodegenerative agents are also proposed. Tg mice overexpressing APP, either normal or mutant, also will provide a powerful tool for examining the influence of other genes that may be involved in Ad, and will allow direct testing of the role of the ratio of expression of the different isoforms of APP in Ad. The value of a mouse model for AD warrants this novel approach.